EP0625146A1 - Säureanhydride, ihre herstellung und ihre verwendung. - Google Patents

Säureanhydride, ihre herstellung und ihre verwendung.

Info

Publication number
EP0625146A1
EP0625146A1 EP93904151A EP93904151A EP0625146A1 EP 0625146 A1 EP0625146 A1 EP 0625146A1 EP 93904151 A EP93904151 A EP 93904151A EP 93904151 A EP93904151 A EP 93904151A EP 0625146 A1 EP0625146 A1 EP 0625146A1
Authority
EP
European Patent Office
Prior art keywords
radical
general formula
tert
hydrogen atom
ococ
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP93904151A
Other languages
English (en)
French (fr)
Other versions
EP0625146B1 (de
Inventor
Jean-Manuel Mas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0625146A1 publication Critical patent/EP0625146A1/de
Application granted granted Critical
Publication of EP0625146B1 publication Critical patent/EP0625146B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new anhydrides of general formula:
  • - Ar represents an aryl radical
  • Rj represents a benzoyl or t.butoxycarbonyl radical
  • R2 represents a hydrogen atom
  • R3 represents a protecting group for the hydroxy function
  • R j represents a t.butoxycarbonyl radical and R2 and R3 together form a saturated heterocycle with 5 or 6 members.
  • Ar represents an optionally substituted phenyl or a- or ⁇ -naphthyl radical, the substituents being able to be chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, aryl, arylalkyl and alkoxy radicals , alcoylthio, aryloxy, arylthio, hydroxy, mercapto, acylamino, aroylamino, alkoxycarbonylamino, amino, alcoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, cyano, nitro and trifluoromethyl being radicals other than the radicals, the radicals being radicals other than the radicals that the radicals are radicals 1 to 4 carbon atoms and the aryl radicals are phenyl or ⁇ - or ⁇ -naphthyl radicals.
  • Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino radical.
  • R3 represents a protecting group for the hydroxy function chosen from the methoxymethyl, 1-ethoxy-ethyl, benzyl-oxymethyl, ( ⁇ -trimethylsilylethoxy) methyl, tetrahydropyrannyl, 2,2,2-ethoxymethyl or 2-trichloro radicals. , 2,2 ethoxycarbonyl. More particularly, when R2 and R3 together form a 5 or 6-membered saturated heterocycle, this represents an oxazolidine ring optionally gem-disubstituted in position -2.
  • the first inventive new hydrides of the formula generated can be held by the action of dration such as an ide corn ... the dicyclohexylcarbodiimide on the acid of general formula:
  • the reac> n is carried out ⁇ - an organic solvent chosen from aliph ues hydrocarbons h aogenated such as dichlorome: u chloroform and aromatic hydrocarbons such as benzene, tolut or xylenes.
  • the reaction is carried out at a temperature between 0 and 30 ° C.
  • the anhydride obtained can be separated from the reaction mixture according to the usual techniques. However, it may be particularly advantageous to use the anhydride obtained prepared extemporaneously without isolation prior to its use in particular in esté ⁇ fication reactions.
  • the anhydrides of general formula (I) are generally more stable than the acids from which they are involved in the esterification reactions and they can lead to more easily reproducible reactions.
  • the new anhydrides of general formula (I) are particularly useful for preparing taxol or taxotere or their derivatives of general formula:
  • OCOC 6 H 5 in which R represents a hydrogen atom or an acetyl radical and Rj and Ar are defined as above, which have particularly advantageous anti-tumor properties.
  • Rj represents a benzoyl or t.butoxycarbonyl radical
  • R2 represents a hydrogen atom
  • R3 represents a protective group for the hydroxy function, on a derivative of baccatin III or 10-deacetyl baccatin III of general formula:
  • G represents a protecting group for the hydroxy function such as a 2,2,2-trichloroethoxycarbonyl or trialkylsilyl radical in which each alkyl part contains 1 to 4 carbon atoms and G2 represents an acetyl radical or a group protector of the hydroxy function such as a 2,2,2-trichloroethoxycarbonyl radical, in order to obtain a product of general formula:
  • the esterification of the alcohol of general formula (IV) is generally carried out in the presence of an activating agent such as an aminopyridine such as 4-dimethylamino pyridine, operating in an organic solvent such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between 0 and 90 ° C.
  • an activating agent such as an aminopyridine such as 4-dimethylamino pyridine
  • an organic solvent such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between 0 and 90 ° C.
  • an activating agent such as an aminopyridine such as 4-dimethylamino pyridine
  • organic solvent such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlor
  • the protective groups G ⁇ , G2 and R3 their replacement with hydrogen atoms can be carried out using zinc in the presence of acetic acid or a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms in the presence of zinc when the protective groups represent at least one 2,2,2,2-trichloroethoxycarbonyl radical, either by means of an acid such as hydrochloric acid in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature in the region of 0 ° C when the protective groups represent at least one trialkylsilyl radical.
  • acetic acid or a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms in the presence of zinc when the protective groups represent at least one 2,2,2,2-trichloroethoxycarbonyl radical, either by means of an acid such as hydrochloric acid in an aliphatic alcohol containing 1 to 3
  • the protective group R3 represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, ( ⁇ -trimethylsilylethoxy) methyl or tetrahydropyranyl radical
  • Gj represents a protective group for the hydroxy function, preferably a 2,2,2-trichloroethoxycarbonyl radical and G2 represents an acetyl radical or a protective group for the functional hydroxy, such as the 2,2,2,2-ethoxycarbonyl trichloro radical, which is treated with a compound which makes it possible to introduce, on the amino function, a benzoyl or t.butoxycarbonyl radical to obtain a product of general formula (VI) in which Ar, Gi and G2 are defined as above, the protective groups G] and G2 of which are replaced by hydrogen atoms under the conditions described above.
  • VI general formula
  • esterification of the product of general formula (IV) is carried out in the presence of an activating agent such as an aminopyridine such as 4-dimethylamino pyridine by operating in an organic solvent such as benzene, toluene , xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between 0 and 90 ° C.
  • an activating agent such as an aminopyridine such as 4-dimethylamino pyridine
  • an organic solvent such as benzene, toluene , xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between 0 and 90 ° C.
  • anhydride of general formula (I) is used per mole of alcohol of general formula (IV).
  • 0.1 to 1 mole of activating agent is used per mole of alcohol of general formula (IV).
  • the product of general fornr.:the (VII) is obtained by treating the product of general formula (V) in which Ar is defined as above, Rj represents a radical t.butoxycarbonyl and R2 and R3 together form a hetero r o ⁇ 5 or 6-membered saturated cycle, optionally with formic acid in an alcohol such as ethanol or with gaseous hydrochloric acid in an alcohol such as ethanol.
  • the reaction mixture is stirred for 40 minutes, allowing the temperature to rise to around 20 ° C.
  • the dicyclohexylurea formed is separated by filtration under an inert atmosphere and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 30 ° C.
  • the solution obtained is added, in 8 hours, to a solution of 21 g of 4-acetoxy-benzoyloxy-2 ⁇ epoxy-5 ⁇ , 20 dihydroxy-l, 13 ⁇ oxo-9 bis- (trichloro -2.2.2 ethoxy) carbonyloxy-7 ⁇ , 10 ⁇ taxene-11 grading 95% (2.24 x 10 " ⁇ mole) and 0.61 g of 4-dimethylamino pyridine in 84 cm3 of dry toluene at 75 ° C .
  • the mixture is further stirred for 2 hours after the end of the addition.
  • the dicyclohexylurea is separated by filtration.
  • the filtrate is concentrated to dryness and the residue is taken up in 150 cm3 of cyclohexane.
  • the solution is poured onto 350 cm3 of heptane cooled to a temperature between 1 and 5 ° C.
  • the precipitate formed is separated by filtration, washed with cold heptane and then dried under reduced pressure.
  • the reaction mixture is stirred for 35 minutes.
  • the dicyclohexylurea formed is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 30 ° C.
  • the present invention also relates to the products of general formula (III) when they are obtained by a process using an anhydride of general formula (I).
  • the present invention also relates to the anti-tumor compositions which contain a product of general formula (III) when it is obtained by a process using an anhydride of general formula (I).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP93904151A 1992-02-07 1993-02-04 Säureanhydride, ihre herstellung und ihre verwendung Expired - Lifetime EP0625146B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9201380 1992-02-07
FR9201380A FR2687145B1 (fr) 1992-02-07 1992-02-07 Nouveaux anhydrides d'acides, leur preparation et leur emplot et
PCT/FR1993/000111 WO1993016058A1 (fr) 1992-02-07 1993-02-04 Nouveaux anhydrides d'acides, leur preparation et leur emploi

Publications (2)

Publication Number Publication Date
EP0625146A1 true EP0625146A1 (de) 1994-11-23
EP0625146B1 EP0625146B1 (de) 1996-12-18

Family

ID=9426425

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93904151A Expired - Lifetime EP0625146B1 (de) 1992-02-07 1993-02-04 Säureanhydride, ihre herstellung und ihre verwendung

Country Status (24)

Country Link
US (1) US5606068A (de)
EP (1) EP0625146B1 (de)
JP (1) JP2894636B2 (de)
KR (1) KR950700266A (de)
AT (1) ATE146463T1 (de)
AU (1) AU686096B2 (de)
CA (1) CA2126461C (de)
CZ (1) CZ283542B6 (de)
DE (1) DE69306760T2 (de)
DK (1) DK0625146T3 (de)
ES (1) ES2095041T3 (de)
FI (1) FI109790B (de)
FR (1) FR2687145B1 (de)
GR (1) GR3022102T3 (de)
HU (1) HU212418B (de)
MX (1) MX9300585A (de)
NO (1) NO304310B1 (de)
NZ (1) NZ249163A (de)
PL (2) PL171713B1 (de)
RU (1) RU2104274C1 (de)
SK (1) SK280329B6 (de)
TW (1) TW254933B (de)
WO (1) WO1993016058A1 (de)
ZA (1) ZA93822B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7288665B1 (en) 1997-08-18 2007-10-30 Florida State University Process for selective derivatization of taxanes
CA2385528C (en) 1999-10-01 2013-12-10 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
US20040132991A1 (en) * 2002-10-09 2004-07-08 Phytogen Life Sciences Inc. Novel taxanes and methods related to use and preparation thereof
US7202370B2 (en) * 2003-10-27 2007-04-10 Conor Medsystems, Inc. Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2629819B1 (fr) * 1988-04-06 1990-11-16 Rhone Poulenc Sante Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii
FR2629818B1 (fr) * 1988-04-06 1990-11-16 Centre Nat Rech Scient Procede de preparation du taxol
US5175315A (en) * 1989-05-31 1992-12-29 Florida State University Method for preparation of taxol using β-lactam

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9316058A1 *

Also Published As

Publication number Publication date
SK92994A3 (en) 1995-04-12
MX9300585A (es) 1993-08-01
JP2894636B2 (ja) 1999-05-24
DE69306760D1 (de) 1997-01-30
FI943644A (fi) 1994-08-05
TW254933B (de) 1995-08-21
RU94040727A (ru) 1996-06-20
ATE146463T1 (de) 1997-01-15
WO1993016058A1 (fr) 1993-08-19
HU9402002D0 (en) 1994-09-28
DE69306760T2 (de) 1997-06-05
ZA93822B (en) 1993-09-09
NO942896D0 (de) 1994-08-04
JPH07503721A (ja) 1995-04-20
HUT71618A (en) 1996-01-29
EP0625146B1 (de) 1996-12-18
RU2104274C1 (ru) 1998-02-10
PL171667B1 (en) 1997-06-30
AU686096B2 (en) 1998-02-05
GR3022102T3 (en) 1997-03-31
FR2687145A1 (fr) 1993-08-13
SK280329B6 (sk) 1999-11-08
NO942896L (no) 1994-08-04
ES2095041T3 (es) 1997-02-01
CZ187194A3 (en) 1994-12-15
DK0625146T3 (da) 1997-01-06
FI943644A0 (fi) 1994-08-05
PL171713B1 (pl) 1997-06-30
CA2126461A1 (fr) 1993-08-19
AU3504993A (en) 1993-09-03
FI109790B (fi) 2002-10-15
NO304310B1 (no) 1998-11-30
KR950700266A (ko) 1995-01-16
US5606068A (en) 1997-02-25
FR2687145B1 (fr) 1994-03-25
NZ249163A (en) 1997-01-29
CZ283542B6 (cs) 1998-04-15
CA2126461C (fr) 2003-05-13
HU212418B (en) 1996-06-28

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